Frequency and Clinical Correlates of Somatic Ying Yang 1 Mutations in Sporadic Insulinomas

Lichtenauer, Urs; Dalmazi, Guido Di; Slater, Emily P.; Wieland, Thomas; Kuebart, Anne; Schmittfull, Anett; Schwarzmayr, Thomas; Diener, Susanne; Wiese, Dominik; Thasler, Wolfgang E.; Reincke, Martín; Meitinger, Thomas; Schott, M.; Fassnacht, Martin; Bartsch, Detlef K.; Strom, Tim M.; Beuschlein, Felix

doi:10.1210/jc.2015-1100

Cited by 44 publications

(40 citation statements)

References 37 publications

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“…Potential targets and regulators of the miR-7 include Yin Yang 1 (YY1), NF-kB/RELA, and cMyc [22][23][24]. In a recent joint publication, we described a mutation in the transcription factor, YY1, which occurs in insulinoma tumors, thus suggesting a role for this factor in neuroendocrine tumors [25].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine

Heverhagen¹,

Legrand²,

Wagner³

et al. 2017

Neuroendocrinology

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Background/Aims: Neuroendocrine neoplasms of the small intestine (SI-NENs) constitute 25-30% of all gastroenteropancreatic NEN. These tumors arise from enterochromaffin cells, and little is known about their microRNA (miRNA) expression. The purpose of this study was to characterize the expression of miRNAs in SI-NEN and to determine the potential of miRNAs as noninvasive blood-based biomarkers. Methods: miRNA was purified from 15 tumor and 7 control tissue samples, converted to cDNA, and applied to a miScript miRNA PCR. The small nucleolar RNA, SNORD95, was used as an endogenous control. Results: Microarray analysis revealed 7 miRNAs that showed a promising distinction between tumorous and healthy tissue. The miRNAs miR-7-5p and miR-96-5p were clearly upregulated in the tumor compared to the healthy tissue. In contrast, miRNAs miR-9-5p, miR-122-5p, miR-124-3p, miR-143-3p, and miR-144-3p showed a distinct downregulation in the tumor compared to the healthy tissue. These results were validated on a further 15 tumor samples, and the findings held true. As the miR-7-5p was significantly upregulated and revealed a low range across tumor samples, its presence was tested in the sera of 32 tumor patients and 25 healthy controls. Sera from all patients with SI-NENs had significantly higher levels of miR-7-5p than those from the 25 healthy controls (p = 0.0002), whereas there was no correlation with age, gender, or T-stage or UICC stage. Conclusion: The miRNA miR-7-5p may be a promising biomarker test for SI-NEN, which should be validated in a large-scale prospective study.

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Section: Discussionmentioning

confidence: 99%

Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine

Heverhagen¹,

Legrand²,

Wagner³

et al. 2017

Neuroendocrinology

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“…Mutations of PTEN were found in 7.3% of PanNET and more recently mutations in TSC2, 8.8%; PIK3CA, 1.4% were also described (Perren et al 2000. TP53 mutations are rare in PanNET Jiao et al 2011, Cao et al 2013, Francis et al 2013, Cancer Genome Atlas Research 2014, Fernandez-Cuesta et al 2014, Cromer et al 2015, Lichtenauer et al 2015, Witkiewicz et al 2015, Scarpa et al 2017.…”

Section: Cellmentioning

confidence: 99%

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

Domenico

Wiedmer

Perren

2017

Endocrine-Related Cancer

106

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Neuroendocrine tumours (NET) of the gastrointestinal tract and the lung are a rare and heterogeneous group of tumours. The molecular characterization and the clinical classification of these tumours have been evolving slowly and show differences according to organs of origin. Novel technologies such as next-generation sequencing revealed new molecular aspects of NET over the last years. Notably, whole-exome/genome sequencing (WES/WGS) approaches underlined the very low mutation rate of well-differentiated NET of all organs compared to other malignancies, while the engagement of epigenetic changes in driving NET evolution is emerging. Indeed, mutations in genes encoding for proteins directly involved in chromatin remodelling, such as DAXX and ATRX are a frequent event in NET. Epigenetic changes are reversible and targetable; therefore, an attractive target for treatment. The discovery of the mechanisms underlying the epigenetic changes and the implication on gene and miRNA expression in the different subgroups of NET may represent a crucial change in the diagnosis of this disease, reveal new therapy targets and identify predictive markers. Molecular profiles derived from omics data including DNA mutation, methylation, gene and miRNA expression have already shown promising results in distinguishing clinically and molecularly different subtypes of NET. In this review, we recapitulate the major genetic and epigenetic characteristics of pancreatic, lung and small intestinal NET and the affected pathways. We also discuss potential epigenetic mechanisms leading to NET development.

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“…Somatic mutations in TSC2 occur frequently in pancreatic NETs (80). Overview of mutational burden in NETs merged from raw data in (80,85,86,87,98,99,100,104,117,120,121,122,128,136,137). Each dot represents a unique tumor, and the line shows the median number of mutations of each category.…”

Section: Tuberous Sclerosis Complexmentioning

confidence: 99%

“…insulinomas, have been identified with recurrent somatic mutations in YY1. This gene encodes a nuclear transcription factor and the described recurrent mutation Thr372Arg has been shown to result in neomorphic effects and altered transcription (98,99,100). Insulinomas exhibit a low mutational burden and the average amino acid substituting mutations were four per tumor (98,99,100).…”

Section: Genetic Landscape Of Netsmentioning

confidence: 99%

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

Crona

Skogseid

2016

European Journal of Endocrinology

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Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.

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Frequency and Clinical Correlates of Somatic Ying Yang 1 Mutations in Sporadic Insulinomas

Abstract: The somatic Thr372Arg YY1 mutation is a relevant finding in female patients with sporadic insulinomas. The prevalence of this mutation in this Caucasian population is considerably lower compared to that of a recently described Asian cohort.

Cited by 44 publications

References 37 publications

Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine

Overexpression of MicroRNA miR-7-5p Is a Potential Biomarker in Neuroendocrine Neoplasms of the Small Intestine

Genetic and epigenetic drivers of neuroendocrine tumours (NET)

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

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